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Home , Alcoholic hepatitis

Research and Reviews

Alcoholic Disease and Its Relationship with Metabolic Syndrome

JMAJ 53(4): 236–242, 2010

Hiromasa ISHII,*1 Yoshinori HORIE,*2 Yoshiyuki YAMAGISHI,*3 Hirotoshi EBINUMA*3

Abstract Alcoholic (ALD), which occurs from chronic excessive drinking, progresses from initial alcoholic fatty liver to more advanced type such as alcoholic , liver fibrosis, or liver when habitual drinking continues. In general, chance of liver cirrhosis increases after 20 years of chronic heavy drinking, but liver cirrhosis can occur in women after a shorter period of habitual drinking at a lower amount of . Alcoholic liver cirrhosis accounts for approximately 20% of all liver cirrhosis cases. The key treatment is abstinence or substantial cutting down on drinking; the prognosis is poor if the patient continues drinking after being diagnosed with liver cirrhosis. Factors that exert adverse effects on the progression of ALD include gender difference, presence of hepatitis virus, immunologic abnormality, genetic polymorphism of alcohol-metabolizing , and complication of obesity or overweight. Recently, particular attention has been paid to obesity and overweight as risk factors in the progression of ALD. Conditions such as visceral fat accumulation, obesity, and diabetes mellitus underlie the pathologic factor of metabolic syndrome (MetS). In liver, MetS may accompany fatty liver or , with possible progression to liver cirrhosis in some cases. Caution is required for patients with MetS who have a high alcohol intake because alcohol consumption further accelerates the progression of liver lesions.

Key words , Metabolic syndrome, Obesity, NAFLD/NASH

Introduction following hypertension and smoking, as a global disease burden. Organ damage caused by alcohol There are many types of liver disease, but alco- can occur not only in the liver but also in many holic liver disease (ALD) is unique in the way other organs including , pan- that it occurs when the patient habitually con- creas, circulatory organs, cranial nerves, and sumes excessive amounts of alcohol through his blood, which is why the medical and social impact or her own volition. Because alcoholic beverages is great. are popular as a lifestyle habit globally and have This paper provides basic information on been established as part of everyday life, ALD ALD and also discusses metabolic syndrome that occurs as a result of excessive alcohol is (MetS) which is the focus of a specific health an important lifestyle-related disease that is screening/guidance program that begun in April prevalent throughout the world. According to 2008 in Japan as well as the influence of alcohol a WHO estimate, alcohol intake ranks third intake.

*1 Professor Emeritus, Division of and , Keio University School of Medicine, Dept. of Internal Medicine, Tokyo, Japan (As of May 2010). *2 Department of Gatroenterology, Eiju General Hospital, Tokyo, Japan ([email protected]). *3 Division of Gastroenterology and Hepatology, Keio University School of Medicine, Dept. of Internal Medicine, Tokyo, Japan. This article is a revised English version of a paper originally published in the Journal of the Japan Medical Association (Vol.138, No.6, 2009, pages 1107–1112).

236 JMAJ, July/August 2010 — Vol. 53, No. 4 ALCOHOLIC LIVER DISEASE AND ITS RELATIONSHIP WITH METABOLIC SYNDROME

Chronic excessive use of alcohol

Continuous drinking Complete abstinence or Fatty liver Liver cutting down on drinking

Continuous Continuous Cured drinking episode drinking

Abstinence Alcoholic hepatitis Liver cirrhosis

Progression

Hepatocellular carcinoma

Fig. 1 Types of alcoholic liver diseases and progression processes

Major Types of ALD and Their failure, gastrointestinal bleeding, and other con- Characteristic Features in Japan (Fig. 1) ditions occur, frequently accompanied by with- drawal syndrome. At this point, prognosis is poor. The disease initially caused by chronic excessive Common histopathologic findings include alcohol consumption is . It is necrosis, infiltration of polymorpho- said that more than half of regular drinkers nuclear leukocytes, ballooning of , (those who drink alcoholic beverages equivalent , and peri-cellular fibrosis. Labora- of 60 g of or more per day, 5 or more days tory tests commonly reveal hyperbilirubinemia, a week, which corresponds to roughly 0.5 L of aspartate aminotransferase (AST)-dominant Japanese sake, 3 half-litter bottles of beer, 6 shots transaminase elevation (increased AST/alanine of whisky, or 5 glasses of wine or more per day) aminotransferase (ALT) ratio), marked increase eventually develop fatty liver. Fatty liver is a in ␥-glutamyl transpeptidase (GTP), polymor- condition in which triglyceride accumulates in phonuclear leukocytosis, hypertriglyceridemia, hepatocyte, causing the enlargement of hepato- and hyperuricemia. cyte and disturbances of blood circulation within Unlike in European or North American coun- the sinusoids, causing adverse effects on various tries, it is not rare in Japan that patients with metabolic processes within the cells. In recent alcoholic fatty liver have relatively mild symp- years, changes in dietary habits to European/ toms with no serious clinical conditions. Yet, American styles have caused increases in fat when such people continue to drink alcoholic intake among Japanese people. Combined with beverages regularly (in the amount equivalent to excessive alcohol intake and overnutrition, it is 60 g/day or more of ethanol), they are likely to causing more advanced fatty liver among people. develop liver fibrosis, which then progresses to Signs and symptoms found in patients with fatty alcoholic liver fibrosis and, consequently, to liver liver are usually no worse than hepatomegaly cirrhosis. Alcoholic liver cirrhosis reportedly with abdominal fullness and malaise, and even occurs in 10–30% of alcoholics. Our own case asymptomatic cases are not rare. studies showed that cirrhosis occurred frequently When patients with alcoholic fatty liver abruptly among heavy drinkers who have at least 20 years increase their alcohol consumption and remains of drinking history at the consumption level of that way (continuous drinking episode), 10–20% 0.9 L/day or more of sake (100–120 g/day or of them develop alcoholic hepatitis (Fig. 1). Clini- more as ethanol). Among women, however, we cal manifestations of alcoholic hepatitis include found cases of liver cirrhosis with only 12 to 15 upper abdominal pain, , fever, vomiting, years of habitual drinking at the 2/3 of the said and . When progressed, pneumonia, renal level. The recent nationwide survey we con-

JMAJ, July/ August 2010 — Vol. 53, No. 4 237 Ishii H, Horie Y, Yamagishi Y, et al.

AlcםHCVםHCV HBVםAlc HBVםHBV HBV Alc Alc OthersםHCV HCV

12% 14%

(9,126סYe ar 2008 (n (21,769סYe ar 1998 (n

Alcoholic (alc) origin 12% Alcoholic (alc) origin 14% viral origin 6%םviral origin 15% Both alcoholicםBoth alcoholic

Total 27% Total 20%

[Cited from Horie et al. (2009).3]

Fig. 2 Proportion of liver cirrhosis that are of alcoholic origin

ducted has revealed that alcoholic liver cirrhosis return to heavy drinking. Thus, it is often difficult is frequent among those with 30 years or more of to have them maintain abstinence. habitual drinking at the consumption level of Fatty liver improves after about 4 weeks of 0.9 L/day or more of sake while women tend to abstinence, often showing reduction of hepato- develop liver cirrhosis after about 20 years of ha- megaly. Hospitalization is necessary in patients bitual drinking at the 2/3 of the same amount.1 with alcoholic hepatitis or liver fibrosis accom- A case where an alcoholic liver cirrhosis patient panied by abdominal pain, fever, and jaundice. developed without The prognosis is poor for patients with severe complication of has also been alcoholic hepatitis, often requiring multidiscipli- reported. nary therapy (including the use of an artificial According to a recent survey, alcoholic liver liver-support system). cirrhosis accounts for approximately 20% of all Patients with non-compensatory liver cirrho- liver cirrhosis cases (Fig. 2).2,3 The prognosis of sis should be hospitalized and receive the same alcoholic liver cirrhosis varies widely, depending treatment as liver cirrhosis of other pathogenesis. on whether or not abstinence is continued after Additionally, they should be subjected to alcohol diagnosis was established. In our experience, the abstinence education for the purpose of tran- survival rate (at 4.4 years after the diagnosis) was sitioning to the compensatory phase. Alcoholics 35% in patients who continued to drink, whereas are unable to restrain themselves from drinking it was 88% in those who abstained from alcohol. once they start, and therefore they require This clearly shows the importance of abstinence lifestyle guidance to reach the state of complete in ALD treatment. abstinence from alcohol. In contrast, if the patients are not alcoholic and are fully aware of Key Points of ALD Treatment the fact that their disease is derived from their excessive drinking, then, providing guidance to The most important issue in the ALD treatment cut down on drinking may be deemed sufficient, is abstinence and its continuation. In particular, allowing about 0.18 L/day of sake with 2 days of most patients with liver cirrhosis are addicted to abstinence per week. alcohol and therefore have difficulty cutting In patients with liver cirrhosis or when there is down on their drinking; if any drinking, even in a complication of hepatitis virus infection, com- a small amount, is permitted, they are likely to plete abstinence from alcohol is required.

238 JMAJ, July/August 2010 — Vol. 53, No. 4 ALCOHOLIC LIVER DISEASE AND ITS RELATIONSHIP WITH METABOLIC SYNDROME

Table 1 Factors involved in the development and progression of alcoholic liver disease

Primary factors Alcohol metabolism and acetaldehyde Oxidative stress/lipid peroxidation Endotoxin/cytokine (e.g., TNF-␣) Impaired microcirculation Hypoxic state Immune reaction Secondary factors Nutritional factors (hypo-protein, lipid, iron, vitamin deficiency) Overweight/obesity Gender difference Genetic polymorphism of alcohol metabolism-related enzymes (ADH, ALDH, CYP2E1)

[Cited from Ishii (2003).5]

Factors Affecting the Development and will be described. Then, the influence of over- Progression of ALD: Focusing on weight/obesity on the progression of ALD will the effects of nutritional factors and be discussed. obesity/overweight on the progression It has been known that increasing the amount of ALD (Table 1) of fat intake during alcohol consumption also raises the amount of triglyceride in the liver With regard to the developmental mechanisms of accordingly. Because alcohol inhibits the oxida- ALD, until the 1950s alcohol itself was believed tion of fatty acids in liver mitochondria and also to have no direct toxicity. It had been advocated facilitates the triglyceride synthesis from fatty that the undernutrition commonly seen in heavy acids, it should be noted that the consumption of drinkers (nutritional deficiency of protein, vita- both fat and alcohol during a meal augments the mins, etc.) was mainly responsible for hepatic severity of fatty liver in proportion to the amount impairment, which was preventable by adminis- of fat intake.4 tration of choline and methionine. However, It is said that 10 to 30% of people who con- after 1963, new methods of alcohol administra- tinue heavy drinking for a long period actually tion were developed, which showed that steady develop liver cirrhosis, while many drinkers only administration of alcohol could produce experi- develop fatty liver, alcoholic hepatitis, or liver mental alcoholic liver lesions even under suffi- fibrosis without ever developing liver cirrhosis. cient nutrition in rats, hamadryas baboons, and Possible background factors responsible for this human volunteers. Thus, it has been proved that discrepancy include gender difference, presence the direct effect of alcohol intake is responsible of obesity or overweight, complication from for a series of liver lesions beginning from fatty hepatic viral infection, influences of gene poly- liver to liver cirrhosis.4 morphisms of alcohol/acetaldehyde metabolizing Subsequently, substantial research on the enzymes, and immune abnormality. This paper developmental mechanisms of ALD has been will specifically discuss overweight/obesity as conducted to date. Currently, the mechanisms of modifying factors of ALD in relation to MetS ALD are considered from two different aspects; that has recently attracted a great deal of atten- primary factors, and secondary factors that tion or in relation to nonalcoholic fatty liver dis- modify the progression of the pathologic con- ease (NAFLD) and nonalcoholic steatohepatitis dition (Table 1).5 For more details, readers are (NASH). advised to refer to other literature.4,5 Upon examining the liver biopsies from 152 In this section, among various nutritional alcoholics, Iturriaga et al.6 pointed out that the factors involved in the progression of ALD, period of drinking, age, and body weight are first the effects of quantitative changes in fat important factors that are correlated with the his-

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tologic stages. In particular, they emphasized that and interleukins by both alcohol and obesity may ALD advances as percent overweight increases act to reinforce the cytotoxicity.10 and regarded obesity as a risk factor in the pro- gression of ALD. Relationship between NAFLD/NASH In a clinical study covering a much larger and Liver Injury in Metabolic Syndrome population conducted in France, Naveau et al.7 (MetS) performed liver biopsies in 1,604 alcoholics and analyzed the correlation between their histo- The concept of MetS was first proposed by WHO pathologic features and the risk factors of ALD in 1990. In April 2005, the MetS diagnostic crite- progression (age, gender, alcohol consumption ria for Japanese people were issued after discus- per day during the past 5 years, duration of sions by eight related academic societies in Japan. habitual drinking, and percent obesity). They In general, a diagnosis of MetS is based on a waist reported that obesity and overweight each circumference exceeding the reference value in served as independent risk factors for fatty liver combination with abnormalities in at least two (402 cases), alcoholic hepatitis (119 cases), and of the three items, namely blood glucose, blood liver cirrhosis (608 cases) among various types of pressure, and blood lipid. Obesity, visceral fat ALD; the liver lesions in those patients were 2.5, accumulation, and insulin resistance are present 3, and 2.5 times more likely to progress to more in the background of MetS. Since liver lesions can advanced state compared to those who were not accompany fatty liver, necrotizing inflammation obese or overweight. of the parenchyma, and fibrosis, MetS and In addition, Ruhl et al.8 extracted data on NAFLD/NASH are considered to be closely alcohol intake and overweight status as factors correlated and that NAFLD and NASH repre- related to fatty liver from the National Health sent certain phenotypes of MetS in the liver. and Nutrition Examination Survey that covered However, not all liver lesions in MetS develop 13,580 adults, in order to investigate the relation into NAFLD or NASH. One explanation for this of these factors to the elevation of AST and ALT is that a diagnosis of NAFLD or NASH requires levels. Their study found that alcohol intake of no alcohol intake (or 20 g/day or less of alcohol), 1–2 drinks per day (12–24 g of alcohol on average) while some MetS patients are drinkers. In the resulted in high frequencies of abnormal AST USA in particular, it is said that a half to 2/3 of and ALT levels in obese or overweight people the current population are overweight or obese. in comparison with people of normal weight. As Given these circumstances, it is likely that the shown in these studies, the incidence of ALD combination of obesity-related fatty liver and accompanied by obesity is on the increase recently, alcoholic fatty liver is increasing.8 and it has become more apparent that the exces- It is a well-known fact that liver lesions in sive nutrition is deeply involved in the progres- obese or overweight persons demonstrate find- sion of various pathologic conditions (fatty liver, ings similar to those in ALD. Therefore, it is quite hepatitis, liver fibrosis, and liver cirrhosis) of ALD. possible that liver lesions in obese patients who The mechanism of involvement of excessive have high levels of alcohol intake may progress nutrition in ALD has not been fully clarified. additively and synergistically with the effects of However, it has been suggested that in ALD alcohol. patients with obesity a large amount of free fatty On the other hand, the frequency of hepatic acids derived from visceral fat enter the liver, dysfunction in nondrinkers who are considered which induces cytochrome P4502E1 (CYP2E1) to have MetS upon health examination is reported in hepatic microsomes, resulting in the produc- to be about 20%. Considering the fact that the tion of highly reactive free radicals and lipid frequency of hepatic dysfunction in nondrinkers peroxides that exert cytotoxicity.9 Since alcohol who are determined to have no MetS is about itself, as is known widely, induces CYP2E1, it is 4%, the obtained odds ratio is 5.6, suggesting that possible that active oxygen species derived from people with MetS can be regarded as future alcohol are also increased, causing increased NASH patients.11 cytotoxicity in an additive or synergistic fashion. In future, it is necessary to further clarify the Furthermore, it is also possible that increased situation of drinkers and nondrinkers among inflammatory cytokines such as TNF-␣, MCP-1, people with MetS. More detailed analysis is also

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desirable concerning the actual drinking habits in Cautions for people with obesity or such patients with NAFLD and NASH. tendency One gram of alcohol has an energy value of Guidance for People with MetS 7.1 kcal. In addition, some alcoholic beverages may contain carbohydrates and small amounts Alcohol exerts a variety of effects on energy of protein and amino acids. Fermented liquors metabolism, lipid metabolism, and carbohydrate such as beer, sake, and sweet wine are common metabolism, serving as a source of energy and examples of such beverages. These drinks have as an agent with various pharmacologic proper- higher calories than distilled liquors with the ties. Therefore, providing drinking guidance same alcoholic content. For instance, a medium would likely be an important aspect in the MetS bottle (500 mL) of beer and a double shot treatment. (60 mL) of whiskey contain an almost equal According to previous reports, alcohol does amount of alcohol (20 g). However, there is a not have substantial adverse effects on MetS, great difference between the two in calories whereas the benefits of alcohol on the living (beer 210 kcal, whiskey 140 kcal), and this differ- body, including the anti-atherosclerotic effect, ence increases as the amount increases. When elevated levels of high-density lipoprotein cho- providing health guidance, this issue should be lesterol, and the blood pressure-lowering effect, borne in mind.14 have been suggested.12,13 However, it is note- worthy that such effects vary widely according Problems of drinking in diabetic patients to the level of alcohol consumption. The benefits Although alcohol exerts various effects on glu- of alcohol are found only when a small amount cose metabolism, the clinical problem of alcohol is consumed. When the serum triglyceride and intake in patients with diabetes mellitus is an blood glucose levels are well controlled, alcohol increased risk of disordered dietary habits result- exerts its benefits at a dose of 20–30 g/day or less ing from chronic alcohol consumption. It has in men and 10–20 g/day or less in women. It is been shown that regular drinking above the level reported that higher levels of alcohol intake of 0.5–1 g/day of alcohol per 1 kg of body weight causes elevation in the triglyceride and blood (equivalent of 30–60 g/day in a person weighing glucose levels and blood pressure in proportion 60 kg) negatively affect blood glucose control. to the increase in the intake. Furthermore, by Furthermore, even greater caution is necessary no means the above mentioned drinking levels for diabetic patients who are taking a hypogly- should be recommended to the people with no cemic drug because chronic alcohol consumption drinking habit. induces a drug-metabolizing (CYP2E1) The main points of providing drinking guid- in hepatic microsomes and elevates the meta- ance for specific cases are described below.14 bolic rate of sulfonylurea drugs to shorten the drug efficacy period. Additionally, when a dia- People who must not drink alcohol betic patient takes a hypoglycemic drug in intoxi- Drinking should be prohibited in alcoholics, cated condition without an adequate meal, the patients with advanced alcoholic organ damage competitive metabolism of the drug and alcohol (e.g., liver cirrhosis, chronic , cardio- can prolong the pharmacologic effect, leading to myopathy), pregnant women, minors, and certain hypoglycemic episode. For specific cautions in other cases. diabetic patients with hypertension or hyperlipi- demia, please refer to other literature.14

References

1. Horie Y, Ishii H. Recent trend of alcoholic liver injury: a new drinking and viral hepatitis type C in the progression of liver development in research of the etiology and pathologic status. cirrhosis. Japanese Journal of Alcohol Studies & Drug Depen- Journal of Adult Diseases. 2009;39:338–346. (in Japanese) dence. 2009;44:38–42. (in Japanese) 2. Ishii H, Miura S. Trend of liver diseases in the light of lifestyle 4. Lieber CS. Alcoholic fatty liver: its pathogenesis and mechanism habits. Journal of Adult Diseases. 2009;39:327–337. (in Japanese) of progression to inflammation and fibrosis. Alcohol. 2004;34: 3. Horie Y, Yamagishi Y, Kikuchi M, et al. Influence of habitual 9–19.

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5. Ishii H. Alcoholic liver disease: the etiologic mechanism and and Related Disorders. Bath: Blackwell Publishing; 2005:281. clinical features. Journal of the Japanese Society of Internal 11. Nishihara T, Ono M, Onishi S. NASH and metabolic syndrome. Medicine. 2003;92:1623–1637. (in Japanese) Japanese Journal of Clinical Medicine. 2006;64:1165–1167. 6. Iturriaga H, Bunout D, Hirsch S, et al. Overweight as a risk factor (in Japanese) or a predictive sign of histological liver damage in alcoholics. 12. Sozio MS, Chalasani N, Liangpunsakul S. What advice should Am J Clin Nutr. 1988;47:235–238. be given to patients with NAFLD about the consumption of 7. Naveau S, Giraud V, Borotto E, et al. Excess weight risk factor alcohol? Nat Clin Pract Gastroenterol Hepatol. 2009;6:18–19. for alcoholic liver disease. Hepatology. 1997;25:108–111. 13. Liu L, Wang Y, Lam KS, et al. Moderate wine consumption in the 8. Ruhl CE, Everhart JE. Joint effects of body weight and alcohol on prevention of metabolic syndrome and its related medical com- elevated serum alanine aminotransferase in the United States plications. Endocr Metab Immune Disord Drug Targets. 2008;8: population. Clin Gastroenterol Hepatol. 2005;3:1260–1268. 89–98. 9. Lieber CS. CYP2E1: from ASH to NASH. Hepatol Res. 2004; 14. Ishii H. The significance and means to limit alcohol consumption. 28:1–11. Journal of Japan Medical Association. 2007;136 (Special Issue 1): 10. Farrell GC, George J, Hall PM, et al. Fatty Liver Disease: NASH S213–S216.

Special notice (message of condolence) We wish to dedicate this paper to the memory of Dr. Hiromasa Ishii, who passed away on May 31, 2010, while the paper was in press.

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